Is ESR1 p.Pro136Ser (c.406C>T) pathogenic?

ESR1 p.Pro136Ser (c.406C>T) is classified Likely benign in ESR1 (ClinVar, Single submitter, 2 submitters; last evaluated 2019-12-31). AlphaMissense: likely benign (0.0687); Rare (popmax 0.405%, afr).

How common is ESR1 p.Pro136Ser (c.406C>T) in the general population?

ESR1 p.Pro136Ser (c.406C>T) is rare (popmax 0.405%, afr) (gnomAD).

What do computational predictors say about ESR1 p.Pro136Ser (c.406C>T)?

AlphaMissense predicts likely benign (score 0.0687) — an in-silico prediction, not a clinical call.

ESR1 p.Pro136Ser

c.406C>T · rs201145204 · VCV709059

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0687 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.405%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0687	likely benign
REVEL	0.027	moderately benign-leaning
SaProt	LLR -6.02	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.3	GERP 1.4, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 35 kb · p 0.76 · regional, not allelic
Overall
CADD	17.28	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.405% African / African-American · 299/73,794 alleles

Filtering AF 0.367% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.353%

Overall 0.0215% 335/1,558,834 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.405%	247
Remaining individualsnot grpmax-eligible	0.0283%	3,532
Admixed American	0.0221%	4,523
Middle Eastern	0.0206%	4,856
South Asian	0.00361%	27,705
European (non-Finnish)	0.00026%	385,164

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: ESR1
Protein: p.Pro136Ser
Coding: c.406C>T
MANE Select: NM_000125
dbSNP: rs201145204
Type: single nucleotide variant
Location: chr6:151808318 (GRCh38)
Gene constraint: LOEUF 0.456 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 67.14 · 492 PDB
Residue 136: the 'modulating (transactivation af-1); mediates interaction with macrod1' region; the 'interaction with ddx5; self-association' region

Full ESR1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SYNE1 p.Arg8746Ter Pathogenic/Likely pathogenic ★★ same type
ESR1 p.Lys299Arg Uncertain significance ★★ ⚠ same type
SYNE1 p.Arg8735Leu Uncertain significance ★★ ⚠ same type
SYNE1 p.Arg8738His Uncertain significance ★★ ⚠ same type
SYNE1 p.Arg8746Gln Uncertain significance ★★ same type
SYNE1 p.Arg8782Gln Uncertain significance ★★ same type
SYNE1 p.Arg8782Gly Uncertain significance ★★ same type
SYNE1 p.Asp8725Asn Uncertain significance ★★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/esr1-p-pro136ser (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown